The gamma chain gene of the interleukin-2 receptor (IL2RG) is the disease gene for X-linked severe combined immunodeficiency (SCID). This is the most common of several gene de-fects causing the SCID syndrome, which occurs in 1 in 10,000 to 100,000 births. Males with X-linked SCID generally die of persistent and opportunistic infections in the first year of life unless they are rescued by bone marrow transplantation. New mutations account for a sub-stantial proportion of cases. Detection of IL2RG mutations in SCID males allows: i) definition of X-linked SCID clinical features within the spectrum of all SCID; ii) study of specific muta-tions with regard to frequency and clinical severity; iii) study of functional characteristics of defective gamma chain protein encoded by mutated IL2RG from patinets with SCID; iv) participation in the evolving manage-ment of SCID families, including devising and performing carrier and prenatal testing; v) monitoring utilization of genetic services by X-linked SCID families; and vi) planning new therapeutic approaches. Research efforts have been aimed at mutation detection by single strand conformation polymorphism and dideoxy fingerprinting. A worldwide database of mutations has been set up. IL2RGbase, currently listing 150 independent mutations, two thirds of which were found in this laboratory. Unique genetic features including germ line mosaicism, a branch point A mutation and 5 mutation hot spots have been found. Prenatal monitoring of at-risk pregnancies has allowed for implementation of neonatal bone marrow transplantation, with improved results over typical transplants. Moreover, a new and promising in utero transplantation was achieved through collaboration with Alan Flake, MD. An affected male fetus was treated in utero with paternal CD34+ cells administered intraperitoneally at 17-20 wk of pregnancy. A term, healthy infant, with functional paternal lymphocytes, is now over 2 yr old. Ongoing genotype/phenotype correlation studies will show whether particular subsets of SCID patients are likely to benefit from retroviral gene therapy.